De Novo Design of Selective Quadruplex–Duplex Junction Ligands and Structural Characterisation of Their Binding Mode: Targeting the G4 Hot‐Spot

Abstract

Invited for the cover of this issue are Andrés G. Santana, Carlos González, Juan Luis Asensio and co‐workers at Instituto de Química Orgánica General, Instituto de Química‐Física Rocasolano and Universidad de La Rioja. The image depicts drug selectivity using a metaphor of an arrow hitting a target. Read the full text of the article at 10.1002/chem.202005026.

High-affinity binding at quadruplex–duplex junctions: rather the rule than the exception

“…The energetic penalty of base unstacking is expected to increase with more extended surface areas and the previously noted absence of any ligand intercalation at a putative Q–D junction of a particular Q–D hybrid design may derive from a formed base triad rather than a base pair stacked onto the G-tetrad platform ( 54 ). On the other hand, a recent study reported on simple aromatic hydrocarbon-based ligands to specifically recognize a Q–D junction by exclusively stacking onto the exposed area of the interfacial G-tetrad with a non-invaded Q–D junction ( 23 ). Such a non-intercalative binding mode may again be attributed to the inability of the aromatic hydrocarbons to overcome the energetic cost of forming an intercalation pocket at the junction.…”

“…Although the simultaneous recognition by both ligand moieties was demonstrated, a more detailed structural characterization has not been provided ( 21 , 22 ). Very recently, the binding of simple aminomethyl-substituted aromatic hydrocarbons as well as indoloquinoline, naphthalene diimide, and pyridostatin derivatives to Q–D junctions resulted in first high-resolution structures of corresponding complexes ( 23–26 ). In fact, indoloquinoline-based ligands such as unsubstituted cryptolepine, aminoalkylated SYUIQ-5, and a phenyl-substituted indoloquinoline derivative PIQ-4m recognized the Q–D junction with higher affinity compared to either the free quadruplex or free duplex, suggesting the possibility of a successful ligand design dedicated for selective Q–D targeting ( 25 , 27 ).…”

Structure of i-Motif/Duplex Junctions at Neutral pH

“…In recent years, G-quadruplex/duplex junctions have been extensively studied 8 and found to be an interesting target for selective recognition. 9 However, very little is known about the structure of i-motif/duplex junctions (IDJs), although they are probably as common as those involving G-quadruplexes. 10 One of the difficulties for studying IDJs is that different experimental conditions are usually required for i-motif and duplex formation.…”